EP1519756B1 - Verwendung von perfluoralkylhaltigen metallkomplexen als kontrastmittel im mr-imaging zur darstellung von intravasalen thromben - Google Patents

Verwendung von perfluoralkylhaltigen metallkomplexen als kontrastmittel im mr-imaging zur darstellung von intravasalen thromben Download PDF

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EP1519756B1
EP1519756B1 EP03740431A EP03740431A EP1519756B1 EP 1519756 B1 EP1519756 B1 EP 1519756B1 EP 03740431 A EP03740431 A EP 03740431A EP 03740431 A EP03740431 A EP 03740431A EP 1519756 B1 EP1519756 B1 EP 1519756B1
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EP1519756A2 (de
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Bernd Misselwitz
Johannes Platzek
Yoko Kawata
Hanns-Joachim Weinmann
Takishi Yokawa
Ulrich Niedballa
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds

Definitions

  • the invention relates to the subject matter specified in the claims, that is to say the use of perfluoroalkyl-containing metal complexes having a critical micelle formation concentration ⁇ 10 -3 mol / l, a hydrodynamic micelle diameter (2 Rh)> 1 nm and a plasma proton relaxivity ( R 1 )> 10 l / mmol ⁇ s, as a contrast agent in MR imaging for the presentation of intravascular thrombi.
  • Thrombosis refers to the formation of a blood clot (thrombus) in a blood vessel and the constriction or blockage of this vessel caused thereby.
  • the most common are thromboses in the veins (phlebothrombosis). Affected here are the veins of the lower body (deep leg and pelvic veins).
  • other parts of the circulatory system may also be affected: heart valves, apex, coronary arteries, cerebral vessels, arteries in the intestine, leg arteries and veins of the leg and pelvis, the rectum (hemorrhoids) and the arm. Carrying out the thrombus can lead to a pulmonary embolism, which in the worst case ends fatally.
  • Thrombosis of deep veins is a major socio-medical problem. In Germany 60,000 people are treated each year for thrombosis and its sequelae. In the United States, 48 out of every 100,000 people suffer from acute thrombosis of the deep veins of the leg and pelvis each year. About 12% of all inpatients develop clinically recognized deep leg or pelvic vein thrombosis. Approximately 20% to 30% of all general surgical patients and more than 50% of all patients undergo deep vein thrombosis after orthopedic / trauma surgery. Approximately 1% of these patients have a pulmonary embolism with clinical symptoms (Guidelines on Diagnostics and Therapy in Vascular Surgery). issued by the Board of Dt. Ges. F. Vascular surgery; Lieber ⁇ videverlag, Cologne 1998).
  • thrombosis The crucial mechanisms causing thrombosis were described as early as 1856 by Rudolf Virchow and named after him as Virchow's Triassic. These are damage to the vessel wall, the slowing of blood flow and an increased coagulation tendency of the blood due to a change in the blood composition. While for venous thrombosis (phlebothrombosis) the slowing down of blood flow and an increased coagulation tendency are in the foreground, with the emergence of the rarer arterial thrombosis, the damage to the vessel wall, usually as a result of arteriosclerosis, with the deposition of platelets (thrombocytes) is crucial ,
  • the thrombus remains in its original form only a few days. After a structural change, it is transformed in its final state scarred and the vessel partially again throughout (recanalized).
  • the goal of the therapy is primarily the restoration of blood flow. This therapy depends on the age of the thrombus and is successful only within the first 10 days after the onset of the thrombus.
  • the restoration of blood flow can be done by a drug dissolution of thrombi (thrombolysis).
  • surgical methods are available, either the removal of the occlusion by removal of the clot (thrombectomy) or the bridging of the closed vessel section by a vascular plastic (bypass).
  • thrombosis therapy aims to prevent further growth of the thrombus and avoid long-term consequences or complications.
  • the diagnosis of thrombosis in clinical practice is mainly by imaging techniques.
  • a very suitable method for the detection of a thrombosis as well as for determining its extent is the X-ray examination of the contrast medium (phlebography). Disadvantages are the exposure to ionizing radiation and the side effects associated with iodine-containing contrast agents. Therefore, the initial examination method is included Suspected deep vein thrombosis in many clinical settings, the color-coded duplex sonography (B-scan plus PW Doppier), which is extremely investigator-dependent.
  • Other non-invasive imaging techniques for imaging luminal vascular changes include arteriography, CT angiography and MR angiography, as well as nuclear medicine methods.
  • thrombi can be represented by indium-111 labeled blood cells as an imaging agent (Thakur et al., Thromb. Res. 9: 345, 1976; Powers et al., Neurology 32: 938, 1982).
  • the iodine isotopes J-125 and J-131 are also suitable for imaging purposes (Pang, US 5,011,686, 1991).
  • a widespread label is the Technetium isotope Tc-99m.
  • Sandoz describes in WO 95/20603 paramagnetic DTPA conjugates that are suitable for thrombus imaging.
  • Conjugates of complexes of DTPA, DOTA or DO3A and polypeptides are described by EPIX in WO 01/09188 and EP 1203026 as imaging agents for thrombus imaging.
  • Pilgrimm calls superparamagnetic iron oxides as contrast agents for thrombosis diagnostics using MRI.
  • particulate is the MR contrast agent described in WO 02/22011 for the diagnosis of thrombi.
  • conjugates contain a further constituent (peptide or drug) in addition to the diagnostically effective part, so that side effects, such as a reduced tolerance, often occur.
  • MR-Venography MMR-Venography
  • FKDS color-coded Doppler sonography
  • the venous system can be selectively represented by perfusion-phase subtraction from the data set of a contrast-enhanced 3D MR angiography and visualized directly after injection of a diluted paramagnetic contrast agent via a dorsal vein.
  • MR angiography with conventional, extracellular, paramagnetic substances, a homogeneous vessel contrast is not always achieved, which makes assessment difficult in individual cases.
  • Blood Pool Agents the faster, contrast-enhanced 3D-MRA could be advantageous.
  • TSE T2-turbo spin echo
  • TOF time-of-flight
  • Contrast medium preparations with selective accumulation in intravascular thrombi could localization and degree of Detect disease at an early stage and thus enable targeted therapy and prophylaxis.
  • perfluoroalkyl-containing metal complexes which have a critical micelle formation concentration ⁇ 10 -3 mol / l, a hydrodynamic micelle diameter (2 Rh> 1 nm) and a proton relaxivity in the plasma (R 1 )> 10 l / mmol ⁇ s have, as contrast agents in MR imaging for the preparation of intravascular thrombi are very well suited.
  • the MR images clearly show that plaques and thrombi are clearly distinguishable from each other. This is so important because thrombi can be mobile at a young age and can lead to lethal embolisms.
  • the gadolinium complexes were used, since the gadolinium of all paramagnetic ions has the greatest influence on the signal amplification in the MRI.
  • gadolinium concentrations of at least 50 ⁇ mol / l and at most 2500 ⁇ mol / l are required in the thrombus, where the accumulation of the compound takes place. Imaging can occur after 15 minutes or up to 48 hours after injection of the compounds of the invention. Since the T1 relaxation times of the tissue are mainly influenced by the gadolinium complexes according to the invention, T1-weighted sequences are best able to detect an enhancement in the thrombus.
  • Suitable perfluoroalkyl-containing metal complexes for the use according to the invention are amphiphilic compounds which, as a non-polar part, have a perfluoroalkyl side chain in the molecule which is optionally linked to the overall molecule via a lipophilic linker.
  • the polar part of the compounds according to the invention is formed by one or more metal complexes and optionally further polar groups.
  • these amphiphilic molecules exhibit the characteristics characteristic of classical surfactants (such as sodium dodecyl sulfate, SDS). So they lower the surface tension of the water.
  • CMC critical micelle concentration in mol / l.
  • the CMC can be calculated from the course of the surface tension (c) function obtained.
  • the critical micelle formation concentration of the compounds according to the invention must be ⁇ 10 -3 mol / l, preferably ⁇ 10 -4 mol / l.
  • the amphiphilic compounds according to the invention are associated in solution and are present as aggregates.
  • the size (2 Rh) of such aggregates e.g., micelles, rods, wafers, etc.
  • PCS Photon Correction Spectroscopy
  • the second criterion is therefore the hydrodynamic micelle diameter 2 Rh, which must be> 1 nm.
  • Particularly suitable according to the invention are those perfluoroalkyl-containing metal complexes whose 2 Rh ⁇ 3 nm, very particularly preferably> 4 nm.
  • the third criterion is the proton relaxivity in plasma (R 1 ) at 40 ° C and a field strength of 0.47 Tesla.
  • the relaxivity which is given in [l / mmol ⁇ s], is the quantitative measure for the shortening of the relaxation time T 1 of the protons.
  • the relaxivity must be as high as possible and be> 10 l / mmol ⁇ s, preferably> 13 l / mmol ⁇ s, more preferably> 15 l / mmol ⁇ s.
  • the relaxivity R 1 [l / mmol.s] of the MR contrast agent according to the invention was determined using the Minispec P 20 instrument from Bruker. The measurements were carried out at 40 ° C and a field strength of 0.47 Tesla. From each T1 sequence: 180 ° -TI-90 °, Inversion Recovery, 8 measurement points were recorded. When Medium served bovine plasma from the company Kraeber. The contrast agent concentrations [mmol / l] were between 0.30 and 1.16 in the batches.
  • the metal complex MK 13 of Tab. 1 is used according to the invention.
  • Particularly preferred compounds of the general formula Id are those having the macrocycle K of the general formula IId, IIId, VdB or VIId.
  • the metal complex MK12 of Tab. 1 is used according to the invention.
  • galenic formulations containing paramagnetic and diamagnetic perfluoroalkyl-containing substances can be used.
  • the paramagnetic and diamagnetic substances are preferably dissolved in an aqueous solvent.
  • Suitable paramagnetic perfluoroalkyl-containing compounds in the formulations according to the invention are all the abovementioned metal complexes of the general formulas I, Ia, Ib, Ic and / or Id.
  • the diamagnetic perfluoroalkyl-containing substances are those of the general formula XX (see WO 02/13874): R F -L 2 -B 2 (XX) wherein R F represents a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms, L 2 is a linker and B 2 is a hydrophilic group.
  • the linker L 2 is a direct bond, an -SO 2 - group or a straight or branched carbon chain having up to 20 carbon atoms, which may be substituted with one or more -OH, -COO - , -SO 3 groups and / or optionally one or more -O-, -S-, -CO-, -CONH-, -NHCO-, - CONR 9 -, -NR 9 CO-, -SO 2 -, -PO 4 - -, -NH-, Contains -NR 9 groups, an aryl ring or a piperazine, wherein R 9 is a C 1 - to C 20 -alkyl radical, which in turn may contain one or more O atoms and / or with -COO - or SO 3 groups may be substituted.
  • Suitable diamagnetic perfluoroalkyl-containing compounds are conjugates of cyclodextrin and perfluoroalkyl-containing compounds. These conjugates consist of ⁇ -, ⁇ - or ⁇ -cyclodextrin and compounds of general formula XXII (see WO 02/13874) A 1 -L 3 -R F (XXII) wherein A 1 is an adamantane, biphenyl or anthracene molecule, L 3 is a linker and R F is a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms.
  • the linker L 3 is a straight-chain hydrocarbon chain having 1 to 20 carbon atoms which is represented by one or more oxygen atoms, one or more CO, SO 2, CONH, NHCO, CONR, NRCO, NH, NR groups or a Piperazine may be interrupted, wherein R is a C 1 -C 5 alkyl radical.
  • the gadolinium complexes MK 1-30 listed in Table 1 fulfill the criteria according to the invention.
  • the physical parameters of these metal complexes are listed in Table 1.
  • the measurements were carried out in plasma at 40 ° C and a field strength of 0.47 Tesla.
  • the reaction is poured into a mixture of 800 ml of methylt-butyl ether and 100 ml of acetone and stirred. The rainfall will purified by chromatography on silica gel.
  • the eluent used is a mixture of dichloromethane / methanol and ammonia in a ratio of 2: 2. 1.
  • the product-containing fractions are combined and concentrated.
  • the residue is dissolved in 200 ml of distilled water, adjusted to pH 7.2 with sodium hydroxide and lyophilized.
  • the title compound is obtained as a white foam. Yield: 7.64 g (39% of theory) Water content.
  • the eluent is a mixture of Ethanol / 2-propanol / conc. Ammonia in the ratio 15: 10: 1.
  • the product-containing fractions are combined, concentrated to dryness in vacuo, redissolved in distilled water and freeze-dried.
  • the title compound is obtained as a white foam. Yield: 7.52 g (62.1% of theory) Elemental analysis. Calc .: 33.66 C 3.55 H 25.86 F 12.59 Gd 8,97 N Found .: 33.55 C 3.67 H 25.99 F 12,43 Gd 9.09 N
  • a coagulum fibrin gel
  • a solution of the title compound from Example 21, WO 02/13874, Mk 13, (0.01 and 0.1 mmol Gd / l) is mixed with 0.5 ml PBS and 0.5 ml of a solution of the title compound from Example 21, WO 02/13874, Mk 13, (0.01 and 0.1 mmol Gd / l) and incubated for 16 hours at room temperature.
  • the unbound portion of the compound of the invention is separated from the fibrin by ultrafiltration (1200 g for 30 minutes).
  • the gadolinium content in the fibrin gel is determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES).
  • the binding of the compound according to the invention to the fibrin gel was 79.1% for the 0.01 mmol Gd / I solution and 38.5% for the 0.1 mmol Gd / I solution.
  • Example 5 MRI presentation (in vivo) of a venous thrombus after intravenous administration of the contrast agent in rabbits
  • MR imaging was performed in rabbits with photochemically induced thrombus (PIT).
  • PIT photochemically induced thrombus
  • xenon light 540 nm, 1100 klux, 25 min
  • Rose-Bengal 20 mg / kg
  • thrombus formation was induced in the left femoral vein.
  • the blood flow in the femoral vein was controlled by means of an ultrasound probe.
  • the left femoral vein (with thrombus) was dissected out, fixed in formalin, and stained for histological evaluation with hematoxylin / eosin (HE) and phosphotungstic acid / hematoxylin (PTAH), respectively.
  • HE hematoxylin / eosin
  • PTAH phosphotungstic acid / hematoxylin
  • FIG. 1 In MR Imaging (MRA) the thrombus was detectable early (25 min pi).
  • Figures 1 and 2 shown in Figure 1 show MR images of the pelvic region 24 h after intravenous administration of 0.1 mmol Gd / kg body weight of the compound of the invention in the PIT rabbit (photochemically induced thrombus).
  • the T 1 -weighted 3D Flash sequence shows a strong signal increase in the thrombus in the area of the left femoral vein. The blood flow in the left femoral vein is significantly reduced (see MRI with phase contrast sequence).
  • red blood clots could be detected in the area of the left femoral vein.
  • the thrombi fill almost the entire lumen of the blood vessel.
  • the exfoliation of the vascular endothelial cells and the adhesion of the thrombi is clearly visible.
  • the intima and adventitia nuclei have largely disappeared.
  • Example 6 MRI presentation (ex vivo) of a venous thrombus after intravenous administration of the contrast agent in rabbits
  • MR imaging was performed in rabbits with photochemically induced thrombus (PIT).
  • PIT photochemically induced thrombus
  • xenon light 540 nm, 1100 klux, 25 min
  • Rose-Bengal 20 mg / kg
  • thrombus formation was induced in the left femoral vein.
  • TR / TE / ⁇ 300 / 12ms / 90 °, with and without fat suppression.
  • the induced thrombus is clearly visible in the preparation due to the color change.
  • a marked enhancement of the thrombi can be observed with the T1-weighted spin echo sequence (see FIG. 3, FIGS. 5 to 7).
  • Example 7 Determination of gadolinium accumulation in the thrombus after intravenous administration of the contrast agent in rabbits
  • the content was determined in rabbits with photochemically induced thrombus (PIT).
  • PIT photochemically induced thrombus
  • xenon light 540 nm, 1100 klux, 25 min
  • Rose-Bengal 20 mg / kg
  • thrombus formation was induced in the left femoral vein.
  • 24 hours after intravenous administration (about 1 h after thrombus induction) of 0.1 mmol Gd / kg of the title compound from example 21 WO 02/13874 24 hours after intravenous administration (about 1 h after thrombus induction) of 0.1 mmol Gd / kg of the title compound from example 21 WO 02/13874, the animal was killed and various organs and tissues were taken to determine the Gd content: blood , Femoral veins (with and without thrombus), muscle. After digestion of the tissue samples, the gadolinium concentration (ppm) was measured by ICP-AES.
  • the Gd concentration was 63 ppm, in the control vessel, however, only 35 ppm.
  • the blood clot outside the vessel had a high Gd content of 166 ppm.
  • a Gd concentration of 15 ppm was detectable at the time of 24 h pi and in the non-signal-intensified muscle of 10 ppm.

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EP03740431A 2002-07-10 2003-07-05 Verwendung von perfluoralkylhaltigen metallkomplexen als kontrastmittel im mr-imaging zur darstellung von intravasalen thromben Expired - Lifetime EP1519756B1 (de)

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SI200330856T SI1519756T1 (sl) 2002-07-10 2003-07-05 Uporaba kovinskih kompleksov, vsebujočih perfluoroalkil, kot kontrastna sredstva pri MR-slikanju za prikaz intravaskularnih trombusov

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DE10231799 2002-07-10
DE10231799A DE10231799B4 (de) 2002-07-10 2002-07-10 Verwendung von perfluoralkylhaltigen Metallkomplexen als Kontrastmittel im MR-Imaging zur Darstellung von Intravasalen Thromben
PCT/EP2003/007274 WO2004006965A2 (de) 2002-07-10 2003-07-05 Verwendung von perfluoralkylhaltigen metallkomplexen als kontrastmittel im mr-imaging zur darstellung von intravasalen thromben

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EP1519756A2 EP1519756A2 (de) 2005-04-06
EP1519756B1 true EP1519756B1 (de) 2007-05-02

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EP (1) EP1519756B1 (uk)
JP (1) JP2005532404A (uk)
CN (1) CN1668338A (uk)
AR (1) AR041187A1 (uk)
AT (1) ATE361103T1 (uk)
AU (2) AU2003281146A1 (uk)
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CA (1) CA2491933A1 (uk)
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ES (1) ES2285143T3 (uk)
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NO (1) NO20050679L (uk)
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PL (1) PL374027A1 (uk)
PT (1) PT1519756E (uk)
RS (1) RS20050020A (uk)
RU (1) RU2328310C2 (uk)
TW (1) TW200413008A (uk)
UA (1) UA79294C2 (uk)
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DE102006021495A1 (de) * 2006-05-09 2007-11-15 Bayer Schering Pharma Ag Verwendung von perfluoralkylhaltigen Metallkomplexen als Kontrastmittel zur Diagnose der Alzheimer Krankheit
AU2009322164B2 (en) * 2008-12-05 2014-12-18 Molecular Insight Pharmaceuticals, Inc. Technetium-and rhenium-bis(heteroaryl) complexes and methods of use thereof
EP3101012A1 (en) 2015-06-04 2016-12-07 Bayer Pharma Aktiengesellschaft New gadolinium chelate compounds for use in magnetic resonance imaging
JP7034160B2 (ja) 2016-11-28 2022-03-11 バイエル・ファルマ・アクティエンゲゼルシャフト 磁気共鳴画像法に使用するための高緩和度ガドリニウムキレート化合物
CN107445911B (zh) * 2017-06-19 2019-07-05 南京科技职业学院 一种二核含钆磁共振对比剂及其制备与应用
PE20211471A1 (es) 2018-11-23 2021-08-05 Bayer Ag Formulacion de medios de contraste y proceso para prepararlos
CN109867635A (zh) * 2019-02-14 2019-06-11 华东师范大学 一种t1型胶束磁共振成像造影剂及其制备方法
EP4059925A1 (en) 2021-03-15 2022-09-21 Bayer Aktiengesellschaft New contrast agent for use in magnetic resonance imaging
EP4335840A1 (en) 2022-09-09 2024-03-13 Bayer Aktiengesellschaft New contrast agents for use in diagnostic imaging
EP4335462A1 (en) 2022-09-09 2024-03-13 Bayer AG Contrast agents for use in diagnostic computed tomography imaging

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US6019959A (en) * 1997-07-31 2000-02-01 Schering Aktiengesellschaft Oligomeric compounds that contain perfluoroalkyl, process for their production, and their use in NMR diagnosis
DE19914101C1 (de) * 1999-03-22 2000-10-12 Schering Ag Perfluoralkylamide, ihre Herstellung und ihre Verwendung in der Diagnostik
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DE19948651B4 (de) * 1999-09-29 2006-10-05 Schering Ag Para- und diamagnetische perfluorhaltige Verbindungen enthaltende galenische Formulierungen, deren Herstellung und Verwendung
US6565828B2 (en) * 2000-04-07 2003-05-20 Bristol-Myers Squibb Company Macrocyclic chelants for metallopharmaceuticals
DE10066210B4 (de) * 2000-08-11 2008-02-28 Bayer Schering Pharma Ag Verwendung von perfluoralkylhaltigen Metallkomplexen als Kontrastmittel im MR-Imaging zur Darstellung von Plaques
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DE10040381C1 (de) * 2000-08-11 2002-06-06 Schering Ag Perfluoralkylhaltige Komplexe mit Zuckerresten, Verfahren zu deren Herstellung und ihre Verwendung

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CA2491933A1 (en) 2004-01-22
WO2004006965A2 (de) 2004-01-22
ZA200501172B (en) 2006-04-26
ES2285143T3 (es) 2007-11-16
AU2003281150A1 (en) 2004-02-02
NO20050679L (no) 2005-04-08
WO2004006965A3 (de) 2004-07-15
IL165889A0 (en) 2006-01-15
WO2004006979A2 (de) 2004-01-22
RU2328310C2 (ru) 2008-07-10
PL374027A1 (en) 2005-09-19
AU2003281146A1 (en) 2004-02-02
CN1668338A (zh) 2005-09-14
ATE361103T1 (de) 2007-05-15
BR0312552A (pt) 2005-04-26
DE10231799A1 (de) 2004-02-12
AR041187A1 (es) 2005-05-04
RS20050020A (en) 2007-08-03
UA79294C2 (en) 2007-06-11
JP2005532404A (ja) 2005-10-27
RU2005103598A (ru) 2005-11-20
DE50307180D1 (de) 2007-06-14
MXPA04012950A (es) 2005-05-16
EP1519756A2 (de) 2005-04-06
TW200413008A (en) 2004-08-01
DE10231799B4 (de) 2006-10-05
PT1519756E (pt) 2007-07-12
DK1519756T3 (da) 2007-08-13

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